The present invention relates generally to the treatment and prevention of hemorrhagic and ischemia disorders. More specifically, the present invention relates to a method and composition for treating and preventing one or more of hemorrhagic shock, septic shock, hypotension, acidosis, and/or hypovolemia.
Shock is a serious medical condition where the rate of tissue perfusion is insufficient to meet demand for oxygen and nutrients. This hypoperfusion state is a life-threatening medical emergency and one of the leading causes of death for critically ill people. Shock may also lead to many other medical emergencies, such as hypoxia and/or cardiac arrest.
The management of shock requires immediate intervention. Re-establishing perfusion to the organs is the primary goal and is achieved by restoring and maintaining the blood circulating volume, ensuring oxygenation and blood pressure are adequate, achieving and maintaining effective cardiac function, and preventing complications.
The prognosis of shock depends on the underlying cause and the nature and extent of concurrent problems. Hypovolemic, anaphylactic, and neurogenic shock are readily treatable and respond well to medical therapy. Septic shock, however, is a grave condition with a mortality rate between 30% and 50%. The prognosis of cardiogenic shock is even worse.
Shock is said to evolve from reversible to irreversible in experimental hemorrhagic shock involving certain animal species (dogs, rats, mice) that develop intense vasoconstriction of the gut. Death is due to hemorrhagic necrosis of the intestinal lining when shed blood is reinfused. In pigs and humans, this is not seen and cessation of bleeding and restoration of blood volume is usually very effective. Prolonged hypovolemia and hypotension does, however, carry a risk of respiratory and then cardiac arrest. Insufficient perfusion of the brain may be the greatest danger during shock. Urgent treatment is essential for a good prognosis in hypovolemic shock.
Shock, at its most fundamental, can be considered a warm ischemia. Warm ischemia is an absolute or relative shortage of the blood supply to an organ or tissues. Ischemia can also be described as an inadequate flow of blood to a part of the body, caused by constriction or blockage of the blood vessels supplying it. Since oxygen is mainly bound to hemoglobin in red blood cells, insufficient blood supply causes tissue to become hypoxic, or, if no oxygen is supplied at all, anoxic. This can cause necrosis (i.e., cell death). Necrosis due to ischemia usually takes about 3-4 hours.
Tissues that are especially sensitive to inadequate blood supply include the heart, the kidneys, and the brain. Ischemia in brain tissue, for example due to stroke or head injury, causes a process called the ischemic cascade to be unleashed, in which proteolytic enzymes, reactive oxygen species, and other chemicals that are harmful in this context can damage and may ultimately kill brain tissue. Restoration of blood flow after a period of ischemia can actually be more damaging than the ischemia. Reintroduction of oxygen causes a greater production of damaging free radicals, resulting in reperfusion injury. With reperfusion injury, necrosis can be greatly accelerated.
The present standard of care in the initial management of shock includes rapid administration of large volumes of isotonic crystalloid solution, which can be up to several liters in an adult patient. In situations where fluid addition to the vascular system is required, such as for resuscitation, the practice has been to add isotonic fluids in sufficient quantity to replenish vascular fluid volume. In practice, this has often been at a rate of 1:1 as compared to blood loss, and often as high as 3:1 compared to blood loss due to physiologic equilibration of resuscitative fluid between the intravascular and interstitial space. Advantages of this practice were avoidance or reduction in triggering anti-inflammatory response, the provision of oxygen to the cells, and the replenishment of osmotic pressure in the vascular system. On the other hand, large volumes of fluids are required to be administered, and cell death often occurs despite the additions of large volumes of the fluids due to cells lapsing into a regime of anaerobic metabolism from which they could not recover.
A preferred fluid is Ringer's lactate, although normal saline or other similar isotonic crystalloid solutions are also used. Recommended continued treatment is based on the observed response to the initial fluid therapy. American College of Surgeons, 154, 585-588, (1987). As a general rule, guidelines are based on the “three for one” rule. This is based on the long-standing empirical observation that most hemorrhagic shock patients require up to 300 mL of electrolyte solution for each 100 mL of blood lost.
Other isotonic fluid replacement solutions have been used, including isotonic crystalloid solutions mixed with macromolecular solutions of plasma proteins or synthesized molecules with similar oncotic properties (colloids); including albumin, dextran, hetastarch or polygelatin in 0.9% NaCl. Whole blood is also used, but it is expensive, often unavailable and cross matching may delay therapy.
Crystalloids and colloids have been used as volume expanders, but generally must be infused in large volume. Such large volumes may cause peripheral and pulmonary edema. Additionally, the large volume requirements of isotonic fluids means that there are time delays and logistic difficulties associated with vascular delivery of effective therapy.
Hyperosmotic crystalloid and hyperosmotic/hyperoncotic (crystalloid/colloid) formulations have been reported to offer some physiological benefits for the treatment of circulatory shock, including improved efficacy for restoration of overall cardiovascular function in animals and man compared to conventional resuscitation. U.S. Pat. No. 3,993,750. Normalization of circulatory function has been obtained with such solutions. U.S. Pat. No. 4,927,806. Small volumes of salt/concentrated dextran formulations have been shown to rapidly restore and sustain normalization of circulatory function in hemorrhage. Surgery 100, 239-246 (1986) and U.S. Pat. No. 4,908,350. However, there remain some important limitations/side effects.
Hypertonic saline infusions in shocked animals and patients have been shown to cause an initial acidosis and hypokalemia. Treatment with hypertonic saline can also lead to a hyperchloremic acidosis, possibly due to excessive chloride load. Some isotonic Ringers solutions and mildly hypertonic formulations mimic sodium and chloride concentration ratios found in plasma and are thought to decrease the likelihood of acidosis. U.S. Pat. No. 3,993,750. Circulatory shock is often associated with an acidosis and, therefore, increased acidotic insult may be deleterious.
Although hypertonic saline rapidly improves both blood pressure and cardiac output, these beneficial effects may be overshadowed by deleterious effects from increased blood pressure. Uncontrolled internal bleeding in trauma patients may be aggravated by increased pressure, leading to increased bleeding. Return of normal blood pressure resulting in increased bleeding due to arterial pressure increase may lead to increased mortality over no treatment. Therefore, ideal pre-hospital resuscitation would increase cardiac output but only modestly increase blood pressure.
Another aspect of resuscitation fluids is their use under less than ideal (non-hospital) conditions. Logistic restraints may severely curtail transportation of weighty or voluminous material. In battlefield situations it may be impractical to administer large volumes, yet there is a critical need to rapidly restore oxygen delivery to critical organs and to prevent or reverse the effects of traumatic shock.